A preliminary study suggests that use of a drug that inhibits a specific protein in patients with certain genetic variants that increase their risk for heart attack reduced their levels of inflammatory markers associated with heart attack risk, according to a study in the May 11 issue of JAMA.
Myocardial infarction (MI – heart attack) is one of the leading causes of death in the world, according to background information in the article. The researchers in this study previously reported the identification of a gene variant that predisposes patients to MI. The gene encodes the 5-lipoxygenase activating protein (FLAP) and its risk variant results in an almost 2-fold increased risk of MI.
Hakon Hakonarson, M.D., Ph.D., of Decode genetics Inc., Reykjavik, Iceland and colleagues conducted a study to determine whether the biological perturbation (disruption) caused by the gene variants that predispose patients to MI through the leukotriene (an inflammatory protein) pathway could be compensated by inhibiting FLAP. The branch of the leukotriene pathway linked to risk of MI, through the activity of FLAP, leads to the production of leukotriene B4, which is a potent mediator of arterial inflammation. The researchers' previously published findings indicate that MI patients, both those with and without the at-risk variants of the FLAP gene, produce more leukotriene B4 than do controls. This suggests that the up-regulation of the leukotriene pathway contributes to risk of the disease, both through genetic and environmental factors, primarily, the researchers believe, by promoting inflammation in atherosclerotic plaques and increasing their propensity to rupture. By inhibiting the function of FLAP and thereby down-regulating the activity of the leukotriene pathway, the risk of MI may be decreased. Of several available inhibitors of FLAP, the researchers used DG-031, which had been used in asthma clinical trials and was shown to be safe and well-tolerated.
The trial included MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87 percent) or leukotriene A4 hydrolase (13 percent). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from the Landspitali University Hospital in Iceland until September 2004. Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.
The researchers found that levels of several biomarkers linked to arterial inflammation and risk of MI decreased. In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26 percent and myeloperoxidase was significantly reduced by 12 percent. The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16 percent) at 2 weeks. However, there was a more pronounced reduction (25 percent) in C-reactive protein at the end of the washout period that was significant and persisted for another 4 weeks thereafter. An 8-day, open-label follow-up study with 75 patients with the same genetic and disease profile as in the Phase IIa was conducted to further examine the effect of DG031 on CRP and myeloperoxidase. The results of this study showed that the 750mg/d dose of DG031, when administered as 250 mg 3 times daily resulted in a 38 percent reduction in CRP levels, as well as a 31 percent reduction in myeloperoxidase levels measured 6 hours after dosing on day 8. In both studies, the FLAP inhibitor DG-031 was well-tolerated and was not associated with any serious adverse events.
"When taken together, the data from our MI gene-isolation study and the clinical trial reported herein show that DG-031 is a safe and well-tolerated drug that affects a biochemical defect that confers a relative risk of acute cardiovascular events, which is similar to or greater than that conferred by the top quartile of LDL cholesterol. Our data suggest that DG-031 reduces serum levels of CRP, serum amyloid A, and myeloperoxidase and these effects are in addition to any effects attributed to statins. Our hypothesis is that this will cause reduction in the risk of MI. To put these results in a historical context, we believe the promise of the beneficial role of DG-031 in cardiovascular disease may, at least in part, reflect that of the statins in the late 1980s when it had been shown that they could lower LDL cholesterol but it had not been shown that lowering LDL cholesterol leads to a decrease in the risk of MI. A study examining clinical outcomes is in the planning stages to determine whether DG-031 does indeed affect the risk of MI," the authors conclude.
(JAMA. 2005;293:2245-2256. Available post-embargo at JAMA.com)
Editor's Note: The study was sponsored by Decode genetics Inc. Co-author Gudmundur Thorgeirsson owns stock in Decode genetics. No other authors reported financial disclosures.
Editorial: Translating the Human Genome Project Into Prevention of Myocardial Infarction and Stroke - Getting Close?
In an accompanying editorial, Christopher J. O'Donnell, M.D., M.P.H., of the National Heart, Lung, and Blood Institute, and Massachusetts General Hospital and Harvard Medical School, Boston comments on the strengths and limitations of the Hakonarson et al study.
"… because they were based on surrogate biomarkers rather than hard clinical end points, the study findings should be viewed as preliminary. It is reassuring that DG-031 appeared safe in prior asthma studies. However, clinical conclusions cannot yet be drawn about DG-031 for prevention of MI because the study was not designed to assess the risks and benefits of the study drug for cardiovascular disease outcomes in patients with or without the risk genotype."
Dr. O'Donnell adds that "while the study demonstrates that DG-031 influences levels of inflammatory biomarkers, the role of ALOX5AP genotype in modifying the effect of this drug remains uncertain. Whether the effect of DG-031 on biomarkers and clinical outcomes is genotype-specific can only be determined in large-scale randomized studies that include patients with other genotypic backgrounds of ALOX5AP."
"The clinical trial by Hakonarson et al provides an exciting attempt to translate genetic findings to clinical applications. How close clinicians and researchers are to the promised destination of a genome-based diagnostics and therapeutics for MI and stroke remains uncertain. This phase 2 pharmacogenetic trial and its implications must be interpreted with the same degree of caution as with any newly proposed risk factor. Continued research is warranted to replicate the original ALOX5AP association. Careful attention to proper study design will be essential to make future trials credible. … As with nongenetic risk factors, the emerging evidence will need to be carefully and continuously examined to ensure that the benefits outweigh the risks as genomics-based strategies are tested in clinical trials," concludes Dr. O'Donnell.
(JAMA. 2005;293:2277-2279. Available post-embargo at JAMA.com)
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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